Endogenous depression is thought to be a genetically determined biochemical disorder which results in an inability to deal with stress. This form of depression is oftentimes classified as unipolar depression, which is subclassified into retarded depression and agitated depression. Retarded depression is characterized by psychomotor retardation, where the subject does not interact with the surrounding environment to any extent. Agitated depression is, on the other hand, characterized by increased unproductive activity such as pacing, hand wringing, etc.
Unipolar depression is most likely a disorder resulting from a number of heterogeneous changes in the brain. One school of thought subscribes to the catecholamine theory: that endogenous depression is caused by a reduction in norepinephrine concentration within the vicinity of adrenergic receptor sites in the brain. Another possibility is that endogenous depression is caused by an absolute or relative deficiency in indoleamine, specifically 5-hydroxytryptamine, at receptor sites in the brain.
The course of treatment for endogenous depression is electroconvulsive therapy or drug therapy. The drugs administered for therapeutic treatment of depression include (1) tricyclic antidepressants, (2) monoamine oxidase (MAO) inhibitors, and (3) second-generation antidepressants.
Tricyclic drugs have been the drug of first choice in treating endogenous depression for over three decades. However, these drugs have limited efficacy in that two-thirds of patients receiving tricyclic drugs do not respond favorably. The side effects of the tricyclics are numerous, including cholinergic blockage, cardiac complications, allergic reactions, dry mouth, constipation, blurred vision and tachycardia. The tricyclic drugs are characterized structurally by a three-ringed nucleus. The tricyclic antidepressants include imipramine, desipramine, amitriptyline, nortriptyline, protriptyline, doxepin and trimipramine. These tricyclic structures are metabolized through the mixed-function oxidase system. These metabolites are the pharmacologically active compounds.
The MAO inhibitors have been available for treatment of depression since the 1950's. These compounds are classified either as hydrazides, exemplified by a C--N--N moiety (e.g., phenelzine and isocarboxazid) or a nonhydrazide (e.g., tranylcypromine). These drugs have not gained wide acceptance due to serious side effects.
The so called second-generation drugs are a group of new drugs which include amoxapine, maprotiline, fluoxetine, trazodone and bupropion. Most of these drugs seem to act in the same fashion as the tricyclic drugs.
Antidepressant drugs must cross the blood-brain barrier in pharmacologically effective concentrations. The capillaries of the central nervous system, unlike capillary beds feeding other organs, possess tight junctions with cerebral endothelial cells. Therefore, the human blood-brain barrier is a lipid barrier without pores. Any potential antidepressant drug must be designed such that the compound is able to traverse the blood-brain barrier. Compounds with low lipid solubility as well as many ionized compounds are unable to exit the circulation for entry into the extracellular fluid of the brain. Water soluble compounds will traverse the blood-brain barrier only if a specific membrane transport system exists. In contrast, lipid soluble drugs, in effect, are not hampered by the blood-brain barrier.
The tripeptide MIF, otherwise known as melanocyte stimulating inhibitory factor, which is represented by the chemical formula of prolyl-leucyl-glycinamide or Pro-Leu-Gly-NH.sub.2, has been shown to produce numerous non-endocrine effects on the brain. The MIF tripeptide has also been shown to be active in a number of animal models for depression.
MIF was initially isolated and characterized from bovine hypothalmic extracts (Nair, et al., 1971, Biochem. Biohys. Res. Comm. 43(6): 1376-1381) and rat hypothalmic extracts (Celis, et al., 1971, Proc. Natl. Acad. Sci. USA 68(7): 1428-1433). MIF activity was attributed to inhibiting release of melanocyte stimulating hormone, a pituitary hormone known to stimulate melanin production. Neither disclosure suggests or discloses any potential antidepressant activity for MIF.
U.S. Pat. No. 3,708,593 (issued to N. P. Plotnikoff on Jan. 2, 1973) teaches that MIF exhibits antidepressant activity in mice, as shown by a modified Dopa test (Everett, et al., 1966, Proc. 1.sup.st Int. Sym. Anti-depressant Drugs, p. 164).
U.S. Pat. No. 3,795,738 (issued to N. P. Plotnikoff on Mar. 5, 1974) teaches that MIF, alone or in combination with other known drugs, exhibits increased activity against Parkinson's disease.
U.S. Pat. No. 3,931,184 (issued to C. G. Lex on Jan. 6, 1976) teaches isolation of medicinally pure MIF. A MIF hemihydrate is dissolved in methanol, followed by the addition of diethyl ether, resulting in a white crystalline precipitate of MIF. This pure MIF is collected, washed with ether and dried under vacuum prior to use.
U.S. Pat. No. 4,278,595 (issued to J. H. Cort on Jul. 14, 1981) teaches that practical use of MIF has been hindered because MIF is rapidly metabolized subsequent to administration. Due to this relatively short half-lite of MIF, it has been necessary to administer large quantities of MIF intravenously over prolonged periods to obtain efficacious concentrations. Cort teaches a MIF analog characterized by replacement of Leu with its D-isomer, optionally replacing Pro with pGlu, and optionally alkylating the terminal amide group of Gly-NH.sub.2 to produce a MIF analog. Such an analog may possess similar antidepressant activity as MIF and enhanced stability. Cort teaches a tripeptide having the formula X-D-Leu-NH.sub.2 --CH.sub.2 --CONR.sup.1 R.sup.2, where X is Pro or pGlu and each of R.sup.1 and R.sup.2 independently is H or a lower alkyl, especially methyl or ethyl.
Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH.sub.2) is a brain derived peptide shown to affect passive avoidance in rats (Hayashi, et al., 1983, Brain Res. Bull. 11: 659-662). Various analogs to Tyr-MIF-1 (i.e., substitutions for the Tyr residue, resulting in Ala-MIF-1, Leu-MIF-1 or Phe-MIF-1) were tested for a possible effect on behavioral and motor activities (Hayashi, et al., 1984, Pharmacology Biochemistry & Behavior 21:809-812). Ala-MIF-1 and Phe-MIF-1, but not Leu-MIF-1, affected passive avoidance behavior in rats. None of these peptides were shown to affect motor behavior.
Kastin, et al. (1984, Pharmacology Biochemistry & Behavior 21: 767-771) discloses that MIF-1 and Tyr-MIF-1 are active as antidepressants. The degree of activity was measured by the water wheel test, a modification of the Porolt swim test.
Kastin, et al. (1985, Pharmacology Biochemistry & Behavior 23: 1045-1049) determined that Tyr-MIF-1 and several Tyr-MIF-1 analogs possess antiopiate activity. Along with Tyr-MIF-1, Phe-MIF-1 was active in inhibiting the analgesic effect of morphine in rats.
Banks, et al. (1986, Am. J. Physiol. 251 [Endocrine Metabolism 14]: E477-E482) identifies the carrier-mediated transport system responsible for delivery of Tyr-MIF-1 to the extracellular brain fluid from the circulatory system.
It would be extremely useful to design and generate modified small peptides for treating patients suffering from depression which possess pharmacological activity subsequent to crossing the blood-brain barrier without inducing the side effects inherent in many of approved antidepressant drugs available today.